Processes for preparing L!- or D!-homoalanin-4-yl-(methyl) phosphinic acid and salts thereof by racemate resolution

ABSTRACT

The title compounds are obtained by racemate resolution of D,L-homoalanin-4-yl(methyl)phosphinic acid via precipitation of one of the diastereomeric salts using chiral bases such as quinine or cinchonine. It is possible to increase the yield of desired enantiomer by transformed racemate resolution when the precipitation of the diastereomeric salt takes place with the racemization of the undesired enantiomer in the presence of (hetero)--aromatic aldehydes. The racemization method is also suitable for structurally different optically active amino acids.

This application is a divisional of Ser. No. 08/398,216 filed Mar. 2,1995 now U.S. Pat. No. 5,767,309.

DL!-Homoalanin-4-yl(methyl)phosphinic acid (DL-Ia) and the ammonium saltthereof (DL-Ib) are amino-acid derivatives with herbicidal activity(DE-A-27 17 440). The amino-acid derivatives are active in the L form(L-Ia or L-Ib), whereas the relevant enantiomeric D form is virtuallyinactive (DE-A-2856260). ##STR1##

In order to be able to use the pure active substance, special processeshave been developed to prepare L!-homoalanin-4-yl(methyl)phosphinic acidand the ammonium salt thereof.

According to DE-A-3 920 570 and DE-A-3 923 650, the L form can beobtained by enzymatic transamination. However, the working up of thetransamination solution is technically very elaborate; in addition,large amounts of salt are produced.

According to EP-A-224 880, the pure L form is likewise obtained bystarting from D!-valine in several stages, with an enantioselectivealkylation of R!-3-isopropyl-2,5-dialkoxy-3,6-dihydropyrazines as keyreaction; however, the disadvantages for application on the industrialscale are the difficulty of obtaining the heterocyclic intermediates andthe necessity to use organometallic agents.

In addition, the L form is obtained by asymmetric hydrogenation ofN-substituted 2-amino-4- (methyl) (hydroxy)-phosphino!butenoic acids(EP-A-238954).

It is likewise possible to prepare (L-Ia) starting from L-vinylglycineor (subst.) L-4-vinyl-1,3-oxazolidin-5-ones and methanephosphonousmonoesters (EP-A-546566 and EP-A-346658); however, the chiral precursorsare not easy to obtain.

Furthermore, processes using methanephosphonous diesters are known(EP-A-508298 and EP-A-530506); however, the required phosphorouscomponent is not available in large amounts, which impedesimplementation of this process on the large scale.

Practicable separation of the racemic mixture DL-Ia! into the pureenantiomers by the "classical" precipitation method utilizingdifferences in the solubilities of diastereomeric salts has not beendisclosed to date. Some processes in which racemates can be separatedwith the aid of chiral compounds via diastereomeric salts have beendescribed for structurally different amino acids. Of particular interestin this connection are processes in which the precipitation of adiastereomeric salt of the desired enantiomer is combined withracemization of the undesired enantiomer.

For example, Bull. Chim. Soc. Jap. 56 (1983) 3744-3747 describes thepreparation of D!-phenylglycine from DL!-phenylglycine with the aid ofd!-camphor-10-sulfonic acid as salt former in the presence of aceticacid and salicylaldehyde as racemizing agent in 68% yield and an opticalpurity of 95.9%.

Shiraiwa et al. describe in Chem. Lett. 1990, 233 et seq. a process forpreparing N-methyl- D!-2-phenylglycine from N-methyl-DL!-2-phenylglycine using 1!-camphorsulfonic acid in butanoic acidwithout the addition of aldehydes or ketones. in this case the salt ofthe D-amino acid precipitates while the L-amino acid racemizes.Triethylamine is subsequently used to liberate the D-amino acid from thediastereomeric salt in yields of 71-77%.

U.S. Pat. No. 4,647,692 describes the racemate resolution of the aminoacids 4-hydroxyphenylglycine and 3,4-dihydroxy-phenylglycine byprecipitation using (+)-3-bromocamphor-10-sulfonic acid in the presenceof ketones and organic acids such as acetic acid. This method is alsorecommended in general form for racemate resolution of DL-Ia.

Independently of the above precipitation methods which combine racemateresolution and racemization of the incorrect enantiomer, publicationswhich describe only racemization methods are known:

J. Org. Chem. 48 (1983) 843-846 relates to the racemization of D-aminoacids in acetic acid or other organic carboxylic acids in the presenceof catalytic amounts of aliphatic or aromatic aldehydes.

U.S. Pat. No. 3213106 discloses the racemization of optically activeamino acids in water without the addition of strong bases or acids attemperatures of 150°-250° C.; furthermore, according to JP-42-13445,amino acids can be racemized in water and in the presence of analiphatic aldehyde with metal ion catalysis. The latter racemizationmethods have the disadvantage that the amino acids are partly decomposedat the stated temperatures or the conversion rate is much too low.

Application of the precipitation methods mentioned hereinbefore to theseparation of DL!-homoalanin-4-yl-(methyl)phosphonic acid using d- or1-camphorsulfonic acid or derivatives thereof proves to beimpracticable. For example, it is not possible to separate out thediastereomeric salt of L!-homoalanin-4-yl(methyl)-phosphinic acid andd!-3-bromocamphor-10-sulfonic acid, as is evident from ComparativeExamples A) and B) (see section "Comparative Examples").

The object therefore was to find a racemate resolution process which canbe carried out on the industrial scale and with which the disadvantagesdescribed above are substantially avoided.

The invention relates to a process for preparingL!-homoalanin-4-yl(methyl)phosphinic acid (L acid) and salts thereof orD!-homoalanin-4-yl(methyl)phosphinic acid (D acid) and salts thereoffrom racemic DL!-homoalanin-4-yl(methyl)phosphinic acid (DL acid) orsalts thereof, which comprises

a) reacting DL acid or salt thereof with a chiral base,

b) allowing the salt of the L acid or D acid and of the chiral base tocrystallize out of a solution of the resulting mixture of thediastereomeric salts of D acid, L acid and the chiral base in an aqueousor aqueous-organic solvent in which the salt of the D acid or of the Lacid has a higher solubility than the salt of the L acid or D acid,respectively (racemate resolution) and

c) in the case where the free L acid or D acid is prepared, neutralizingthe resulting salt with an acid, or in the case where a salt other thanthat obtained according to b) is prepared, carrying out a metathesis.

The process according to the invention for preparingL!-homoalanin-4-yl(methyl)phosphonic acid and salts thereof is carriedout with chiral bases, preferably alkaloid bases such as quinine,cinchonidine and brucine. The use of quinine is particularlyadvantageous.

The enantiomers of the said chiral bases, for example quinidine andcinchonine, are suitable for preparingD!-homoalanin-4-yl(methyl)phosphinic acid.

Because of the greater economic importance of the L acid, the processroutes are described hereinafter for the example of the preparation of Lacid. The processes can be used analogously to prepare the D acid byusing the enantiomeric chiral bases.

In order to reduce the solubility of diastereomeric salts of the L! formcompared with the solubility in pure aqueous solutions it is possible touse, for example, solvent mixtures composed of water and organicsolvents which are miscible with water in the particular mixing ratioused. Suitable mixing partners for the aqueousorganic solvent mixturesare, for example, organic solvents from the group consisting of alcoholssuch as, for example, methanol, ethanol, n-propanol, i-propanol,n-butanol, i-butanol, sec-butanol and t-butanol, of ketones such as, forexample, acetone, methyl ethyl ketone, methyl isobutyl ketone andN-methylpyrrolidone, and combinations of the said solvents. It is alsopossible with comparatively small amounts of solvent, i.e. using highlyconcentrated solutions, to use water as sole solvent.

The use of i-propanol or t-butanol in combination with water provesparticularly advantageous.

The optimal temperature for the crystallization depends on the chiralbase, the solvent, the concentration of the salt, the amount of thechiral base and the crystallization rate. It is, as a rule, advantageousto carry out the crystallization at temperatures of 0°-100° C.,preferably 0°-85° C., in particular at 15°-75° C. Suitable and preferredsolvent mixtures are composed of water and alcohols, for examplet-butanol:water in the ratio of, for example, 20:80 to 90:10, preferably50:50 to 85:15, in particular 70:30 to 85:15, or isopropanol:water inthe ratio of 20:80 to 90:10, preferably 50:50 to 90:10, in particular70:30 to 85:15. The latter ratios of amounts preferably apply tocarrying out the crystallization at temperatures of 0°-85° C., inparticular 15°-75° C.

The liberation of the acid (L-Ia) from the diastereomeric salt of thecrystals can take place in analogy to customary methods, for example byneutralization with an organic or inorganic acid, where appropriate in asuitable solvent. The metathesis into another salt can take place byreaction with an excess of an inorganic base which contains the desiredcation, or with an organic base (for example amine base) or ammonia whenoptionally substituted ammonium salts of (L-Ia) are to be prepared.Preparation of the ammonium salt (L-Ib), which can be usedsatisfactorily as herbicide, by metathesis with ammonia is preferred.The reaction with ammonia can be carried out, for example, by dissolvingthe crystals in a suitable solvent such as methanol and passing inammonia or adding a solution of ammonia in a solvent, for examplemethanol again, in excess, and precipitating the ammonium salt (L-Ib).The mother liquor which contains the chiral base can then be returned tothe next batch.

In a preferred procedure for the process according to the invention, theundesired D isomer (D-Ia) or the salt thereof, for example the salt of(D-Ia) with the chiral base, is racemized, and the resulting racemiccompound (DL-Ia) or salt thereof is used for the racemate resolutionaccording to the invention.

Processes suitable in principle for the racemization of (D-Ia) are thosewith which other amino acids can also be racemized. For example, thereferences already mentioned above, Bull. Chim. Soc. Jap. 56 (1983)3744-3747, Chem. Lett. 1990, 233 et seq. and J. Org. Chem. 48 (1983)843-846 disclose the catalysis of racemizations of optically activeamino acids by aldehydes in organic acids.

The racemization may take place separately or with the racemateresolution:

a) Suitable for carrying out the racemization of the D isomer after thecrystallized salt of the L isomer has been separated out are theabovementioned processes (see also Example C in the "ComparativeExamples" section hereinafter). Apart from the additional process stagesin the case of separate racemization, however, the known processesusually have further disadvantages, for example that the racemizationmust take place in the presence of acids. The addition of organic acidshas considerable technical disadvantages for the process when the knownmethod is applied to the racemization of the salt of the D isomer and ofthe chiral base which results according to the invention in the motherliquor of the crystallization stage. Addition of acid means, forexample, a change of the solvent, for which reason the racemizationsolution cannot be returned directly to the next crystallization batchwithout altering the crystallization conditions.

b) If, furthermore, the racemization of the D isomer is to take place inthe same reaction mixture at the same time as the crystallization,according to the invention, of the salt of the L isomer and of thechiral base, the known racemization methods can no longer be applied orare not practicable industrially, as is evident from Comparative ExampleD hereinafter. Although the diastereomeric salt of (D-Ia) and of thechiral base, in this case quinine, can be smoothly racemized in aceticacid in the presence of salicylaldehyde (Comparative Example C), it isimpossible to crystallize the diastereomeric salt of (L-Ia) in aceticacid medium (Comparative Example D).

The organic acids added in the known racemization methods must for theabovementioned reasons be avoided in the preferred combinedcrystallization process according to the invention. Racemization in thepresence of the known aldehydes does not as a rule take place withoutthe addition of acids, i.e. if the intention is to carry out theracemization with the aldehydes in neutral or weakly basic or evenweakly acidic aqueous medium.

Surprisingly, our experiments have shown that the racemization takesplace even in such media when certain aldehydes are used.

The invention therefore also relates to a novel process for theracemization of optically active amino acids, preferably amino acids ofthe formula (D-Ia) and derivatives thereof, which comprises reacting theoptically active amino acids in the presence of six-membered(hetero)aromatic aldehydes which have a hydroxyl group in position 2with respect to the aldehyde group and electron-attracting radicals suchas, for example, NO₂, CN, CF₃ and SO₃ H, in particular NO₂, in position3 or 5 with respect to the aldehyde group and are further substitutedwhere appropriate, in aqueous or aqueous-organic medium.

The racemization according to the invention takes place without theaddition of inorganic or organic acids. Racemization in neutral orweakly basic or weakly acidic medium, for example at pH 4-9, inparticular at pH 5-8, is preferred.

The racemization is, as a rule, carried out at temperatures of 0°-120°C., preferably 30°-85° C., in particular 35°-75° C., depending on thereactivity of the aldehyde.

Preferred aldehydes for the racemization are salicylaldehydes activatedon the phenyl ring by electron-attracting radicals in position 3 or 5,for example nitro groups, and are further substituted where appropriate,for example 5-nitrosalicylaldehyde or 3,5-dinitrosalicylaldehyde.

It is also possible, for example, to use analogous heteroaromaticaldehydes in place of the aromatic aldehydes. It is worth mentioning inthis connection pyridinealdehydes, for example pyridoxal, which may,depending on the substitution pattern, also be immobilized on aninorganic or organic support.

Suitable amino acids are the customary optically active amino acids andsalts thereof, for example D- or L-alanine, substituted D- orL-alanines, substituted glycines such as phenylglycine orhydroxyphenylglycine, and D- or L-leucines etc. and the amino-acidderivatives such as (D-or L-Ia).

The amount of aldehydes used can vary within wide limits and can easilybe optimized in preliminary experiments. The aldehydes are preferablyused in less than the stoichiometric amount based on the amino acid orsalt thereof, in particular in catalytic amounts. As a rule, the amountsof the particular aldehyde are in the range from 0.01 mole to 0.1 moleper mole of amino acid or salt thereof used. If a very small amount ofaldehyde is used, the conversion takes place too slowly for practicalpurposes. The use of excessively large amounts of aldehyde may impairfurther processing of the mixture and also appears to have little sensefrom the economic viewpoint.

A particular advantage of the racemization according to the invention isthat it can be carried out at considerably lower temperatures than wasto be expected. The conversion not only takes place at the temperaturesof 80°-150° C. used in strongly acidic media but can also be carried outat temperatures below 80° C., preferably 35°-75° C., in particular40°-70° C. In contrast to the conventional methods mentioned, these lowtemperatures for the racemate resolution of (DL-Ia) using chiral basesmake it possible to carry out the crystallization of the salt of (L-Ia)and of the chiral base at the same time as the racemization of the saltof (D-Ia) in one mixture.

The various possibilities for carrying out the racemate resolutionaccording to the invention and the racemization of the acid (D-Ia) orsalt thereof according to the invention are explained below.

One possibility comprises, after the crystallization in stage b) of theprocess according to the invention, heating the mother liquor, whichessentially contains the diastereomeric salt of (D-Ia) and residues ofthe diastereomeric salt of (L-Ia), in the presence of one of the saidaldehydes, carrying out the racemization at temperatures of 0°-120° C.,preferably 30°-85° C., in particular 35°-75° C. The salt of theracemized amino acid and of the chiral base can then be returneddirectly, i.e. without working up and without changing the solvent, tothe next crystallization batch.

A combined procedure (alternative 1) as batch process or as continuousprocess for preparing the ammonium salt (L-Ib) starting from theammonium salt (DL-Ib) comprises, for example,

(1) reacting ammonium DL!-homoalanin-4-yl(methyl)-phosphinate with achiral base in a solvent mixture of water and an organic solvent whichsolubilizes the ammonium DL!-homoalanin-4-yl(methyl)-phosphinate, andremoving the liberated ammonia, then

(2) at temperatures of 0°-85° C. allowing the diastereomeric salt ofL!-homoalanin-4-yl(methyl)phosphinic acid and of the chiral base tocrystallize out of a solvent mixture of water and an organic solvent,and isolating it, for example by filtration with suction, andsubsequently

(3) heating the mother liquor from the crystals, which essentiallycontains the other diastereomeric salt of the D!-amino acid and residuesof the diastereomeric salt of the L!-amino acid, in the presence of a(hetero)aromatic aldehyde at temperatures of 20°-120° C. and, after theracemization, passing the resulting solution to the next crystallizationbatch (2) and

(4) reacting the diastereomeric salt ofL!-homoalanin-4-yl(methyl)phosphonic acid and of the chiral base fromstage (2) in the mixture of water and an organic solvent or in theorganic solvent itself with ammonia, whereupon ammoniumL!-homoalanin-4-yl-(methyl)phosphinate (L-Ib) precipitates, isolatingthe precipitated ammonium salt (L-Ib), for example by filtration withsuction, and returning the mother liquor, which essentially contains thechiral base, to stage (1) of the next batch.

It is important for optimization of the combined process to adapt thetemperatures to the particular process step. Temperatures of 20°-100° C.are advantageous in stage (1), whereas the step according to stage (2)is beneficially carried out at 0°-85° C., preferably at 15°-75° C. Thetemperature in stage (3) should be appropriate for the reactivity of thealdehyde. The process according to stage (4) can preferably be carriedout at temperatures of 0°-60° C.

In another possibility, which is particularly preferred, theracemization is carried out in the same stage as the crystallization ofthe diastereomeric salt of (L-Ia). The conditions for thecrystallization in respect of solvent and temperature are theninevitably consistent with those for the racemization; this restrictsthe choice of the racemization processes and, in the case of thementioned racemization with aldehydes, the choice of the possiblealdehydes. As already mentioned above, this combined process is notpracticable using the conventional processes in the presence of acidsand aldehydes but can be carried out using the said inventive processfor racemization using specific aldehydes without the addition of acids.

The inventive variant of the combined process comprises reacting amixture of the diastereomeric salts of D acid and L acid and of thechiral base, dissolved in an aqueous or aqueous-organic solvent in whichthe salt of the D acid has a higher solubility than the salt of the Lacid, at temperatures of 0°-85° C., preferably of 30°-85° C. in thepresence of an aldehyde, the temperature being set sufficiently low forthe salt of the L acid and of the chiral base to crystallize out at thesame time.

It is possible in principle with the preferred combined process(racemate resolution and racemization) to convert (DL-Ia) 100% into(L-Ia). Suitable for the preferred process are the abovementioned chiralbases and the six-membered (hetero) aromatic aldehydes which have ahydroxyl group in position 2 with respect to the aldehyde group andelectron-attracting radicals in position 3 or 5 with respect to thealdehyde group, in particular the bases and aldehydes mentioned aspreferred.

The preferred combined procedure (alternative 2), as batch process or ascontinuous process for the preparation of the ammonium salt (L-Ib)starting from the ammonium salt (DL-Ib), comprises, for example,

(1') reacting ammonium DL!-homoalanin-4-yl(methyl)-phosphinate with achiral base in a solvent mixture of water and an organic solvent whichsolubilizes the ammonium DL!-homoalanin-4-yl(methyl)-phosphinate, andremoving the ammonia, then

(2') reacting with an aromatic aldehyde at temperatures of 0°-85° C.,preferably of 30°-85° C. in the presence of a solvent mixture of waterand organic solvent and, at the same time, allowing the diastereomericsalt of L!-homoalanin-4-yl(methyl)phosphinic acid and of the chiral baseto crystallize out, isolating the crystals, for example by filtrationwith suction, and adding the mother liquor to stage (2') of the nextbatch and

(3') reacting the diastereomeric salt ofL!-homoalanin-4-yl(methyl)phosphinic acid and of the chiral base fromstage (2') in the mixture of water and an organic solvent or in theorganic solvent itself with ammonia, moreover filtering the precipitatedammonium L!-homoalanin-4-yl(methyl)phosphinate with suction, andreturning the mother liquor, which essentially contains the chiral base,to stage (1') of the next batch.

For the process to succeed it is important that the temperatures areadapted to the particular process step. Process steps (1') and (3')substantially correspond to process steps (1) and (4) from the combinedprocess already mentioned above (alternative 1). The process stepaccording to stage (1') is advantageously carried out at temperatures of20°-100° C., whereas the step according to stage (2') is beneficiallycarried out at the temperature at which the diasteromeric salt of (L-Ia)crystallizes out but the racemization of the undesired (D-Ia) stilltakes place sufficiently quickly. Stage (3') is advantageously carriedout at temperatures of 0°-60° C.

A diagrammatic comparison of alternatives 1 and 2 shows, taking theexample of the racemate resolution of (L-Ib), the saving of a processstage in alternative 2 (see Table 1):

                  TABLE 1    ______________________________________    No.     Alternative 1    Alternative 2    ______________________________________    (1)     (DL-Ib) + chiral base                             (DL-Ib) + chiral base    (2)     Removal of NH.sub.3, where                             Removal of NH.sub.3, where            appropriate change                             appropriate change            solvent          solvent    (3)     Crystallization (race-                             Crystallization (race-            mate resolution) mate resolution) and                             reaction with aldehyde    (4)     Filtration       Filtration                             Mother liquor back to                             (3)    (5)     Dissolve crystals and                             Dissolve crystals and            react with NH.sub.3                             react with NH.sub.3    (6)     Filter off product                             Filter off product            (L-Ib), mother liquor                             (L-Ib), mother liquor            back to (1)      back to (1)    (7)     Heat mother liquor from            (4) with aldehyde and            back to (3)    ______________________________________     Re Table 1: (No.) = number of the process operation

It is possible to carry out the individual process steps batchwise orelse continuously. Mother liquors resulting from the use are preferablyreturned to the complete process in order to keep losses of yield small.

Suitable solvents for the process stages described above are thesolvents already mentioned for the crystallization stage. Anadvantageous procedure comprises using the same solvent system in allthe process steps. However, it is sometimes also sensible to vary theproperties of the solvent system simply by adding another solvent to thesolvent from the previous stage.

EXAMPLES

In the following Examples, quantity and percentage data are based onweight unless otherwise indicated. The names "L salt", "D salt" and "D,Lsalt" mean the salt of (L-Ia), (D-Ia) and (D,L-Ia), respectively, and ofthe chiral base.

Example 1

1.1 39.6 g of 99.8% pure ammoniumDL!-homoalanin-4-yl-(methyl)phosphinate (0.2 mole) and 65.5 g of(-)quinine (99% pure) (0.2 mole) are heated to reflux in 210.8 g ofwater. Subsequently 22.6 g of aqueous ammonia are removed by applying areduced pressure of 100 mbar. At 70° C., 766.4 g of tert-butanol andthen 3.38 g of 5-nitrosalicylaldehyde (0.02 mole) are added, and theclear solution is seeded at 50° C. withL!-homoalanin-4-yl(methyl)-phosphinic acid/quinine salt. Thediastereomeric L salt precipitates slowly at 48° C. and below. Themixture is allowed to reach room temperature over the course of 6 hours,and the solid is filtered off with suction, washed with a littletert-butanol/water (80:20) and dried in vacuo at 60° C. This results in41.0 g of L!-homoalanin-4-yl(methyl)-phosphinic acid/quinine salt with apurity of L salt:D salt of 98.7:1.3.

1.2 The mother liquor from Example 1.1 is refluxed for 9 hours (samplemeasurement L:D=50.6:49.4) and added to another 0.2 mole batch inanalogy to Example 1.1 at 70° C. (amount used about 0.319 mole of DL!salt). Crystallization is allowed to occur, and 97.3 g ofL!-homoalanin-4-yl(methyl)phosphinic acid/quinine salt are obtained witha purity of L salt:D salt of 99.5:0.5 (corresponding to 60% of theory).The mother liquor can in turn be added to another batch. The crystalsare taken up in 97.3 g of methanol, and 27.8 g of methanolic ammonia(17.7% strength) (0.29 mole) are added; the crystals which have formedare then filtered off. 36.2 g of ammoniumL!-homoalanin-4-yl(methyl)phosphinate are obtained with an opticalpurity of L:D=99.5:0.5. This corresponds to an isolated yield of 57.0%of theory based on 0.319 mole of DL salt. The mother liquor from thesecrystals, which essentially contains the (-)quinine, is added to anotherbatch.

Example 2

39.6 g of 99.8% pure ammonium DL!-homoalanin-4-yl-(methyl)phosphinate(0.2 mole) and 65.5 g of (-)quinine (99% pure) (0.2 mole) are heated in210.8 g of water; subsequently 24.0 g of aqueous ammonia are removed byapplying a reduced pressure of 100 mbar. At 70° C., 766.4 g oftert-butanol and then 4.3 g of 3,5-dinitrosalicylaldehyde (0.02 mole)are added, the mixture is cooled to 50° C. and the clear solution isseeded with L!-homoalanin-4-yl(methyl)phosphinic acid/quinine salt. Themixture is stirred for 9 to 10 hours, during which the L salt slowlyprecipitates. The mixture is allowed to reach room temperature over thecourse of 6 hours, and the solid is filtered off with suction, washedwith tert-butanol/water (80:20) and dried in vacuo at 60° C. Thisresults in 86.5 g of L!-homoalanin-4-yl(methyl)-phosphinic acid/quininesalt with a purity of L salt:D salt of 99.5:0.5. This corresponds to ayield of 85.1% of theory. The mother liquor is added to another batch at70° C. The crystals are taken up in 86.5 g of methanol, 24.7 g ofmethanolic ammonia (17.7% strength) (0.258 mole) are added, and thecrystals which form are filtered off. 32.2 g of ammoniumL!-homoalanin-4-yl-(methyl)phosphinate are obtained with an opticalpurity of L:D=99.9:1.0. This corresponds to an isolated yield of 80.5%of theory. The mother liquor, which essentially contains the (-)quinine,is added to another batch.

Example 3

3.5 g of ammonium DL!-homoalanin-4-yl(methyl)phosphinate (0.019 mole)and 6.2 g of (-)quinine (0.019 mole) are dissolved in 18.2 g of water at50° C., and 27.4 g of hot acetone are added. A clear solution isobtained at 50° C. It is allowed to cool slowly while seeding the clearsolution with L!-homoalanin-4-yl(methyl)phosphinic acid/quinine salt,and crystallization is allowed to occur. The solid is filtered off withsuction at 20° C. and washed with a little acetone, and the filter cakeis dried at 60° C. in vacuo. 4.0 g ofL!-homoalanin-4-yl-(methyl)phosphinic acid/quinine salt which containsL-amino acid portion and D-amino acid portion in the enantiomeric ratioof 99.8:0.2 are obtained. This corresponds to a yield of 83.3% of theorybased on the use of L form, and 41.7% of theory based on D,L mixtureused.

Example 4

3.5 g of ammonium DL!-homoalanin-4-yl(methyl)phosphinate (0.019 mole)and 6.2 g of (-)quinine (0.019 mole) are dissolved in 18.2 g of water at50° C., and 103.1 g of hot isopropanol are added. A clear solution isobtained at 50° C. It is allowed to cool slowly while seeding the clearsolution with L!-homoalanin-4-yl(methyl)phosphinic acid/quinine salt,and crystallization is allowed to occur. The solid is filtered off withsuction at 20° C. and washed with a little acetone, and the filter cakeis dried at 60° C. in vacuo. 4.2 g ofL!-homoalanin-4-yl-(methyl)phosphinic acid/quinine salt which containsL-amino acid portion and D-amino acid portion in the enantiomeric ratioof 99.8:0.2 are obtained. This corresponds to a yield of 86.3% of theorybased on the use of L form, and 43.2% of theory based on D,L mixtureused.

Example 5

1.1 g of D!-homoalanin-4-yl(methyl)phosphinic acid (D:L=99.5:0.5) (0.006mole), 2.0 g of quinine (0.006 mole) and 0.13 g of3,5-dinitrosalicylaldehyde (0.0006 mole) are dissolved in 5.2 g of waterand 23.0 g of tert-butanol and stirred at 40° C. for 23 hours.DL!-homoalanin-4-yl(methyl)phosphinic acid/quinine salt which containsD-amino acid portion and L-amino acid portion in the enantiomer ratio of50.2:49.8 is obtained.

Example 6

0.8 g L!-tert-leucine (99% pure, 0.006 mole), 2.0 g of quinine (0.006mole) and 0.13 g of 3,5-dinitrosalicylaldehyde (0.0006 mole) aredissolved in 5.2 g of water and 23.0 g of tert-butanol and stirred at50° C. for 24 hours. DL!-tert-leucine which contains D-amino acidportion and L-amino acid portion in the enantiomer ratio of 50.9:49.1 isobtained.

Example 7

3.44 g of DL!-homoalanin-4-yl(methyl)phosphinic acid and 5.6 g ofcinchonine (0.019 mole) are dissolved in 27 ml of water at 50° C., and243 g of tert-butanol are added hot. The solution is seeded withD!-homoalanin-4-yl-(methyl)phosphinic acid and slowly cooled to roomtemperature. 4.5 g of D!-homoalanin-4-yl(methyl)phosphinicacid/cinchonine salt are obtained with an enantiomeric purity ofD:L=96.7:3.3. This corresponds to an isolated yield of 96.2% of theory.

Comparative Examples

A) 90 g of tert-butanol are added to 2.7 g ofDL!-homoalanin-4-yl(methyl)phosphinic acid (0.015 mole), 5.0 g ofammonium (+)-3-bromocamphor-8-sulfonate (0.015 mole) in 10 g ofdemineralized water at 75° C. in such a way that the temperature is keptat 75° C. The mixture is heated under reflux for 1 hour and then slowlyallowed to reach room temperature. Precipitated crystals are filteredoff with suction, washed and dried in vacuo at 50° C. 4.8 g ofhomoalanin-4-yl(methyl)phosphinic acid/(+)-3-bromocamphor-8-sulfonicacid salt are obtained with a diastereomer content of L:D=50:50.

B) 3.0 g of ammonium DL!-homoalanin-4-yl(methyl)-phosphinate (0.015mole), 5.0 g of ammonium (+)-3-bromocamphor-8-sulfonate (0.015 mole) aredissolved in 10 g of demineralized water at 75° C. and, at thistemperature, 135 g of tert-butanol are added. 1.53 g of H₂ SO₄ (96%strength) (0.015 mole) are added, and the mixture is allowed to coolslowly. 3.5 g of homoalanin-4-yl(methyl)phosphinicacid/(+)-3-bromocamphor-8-sulfonic acid salt with a diastereomer contentof L:D=50.1:49.9 are obtained.

C) 2.9 g of D!-homoalanin-4-yl(methyl)phosphinic acid/quinine salt witha D salt:L salt purity of 99.8:0.2 (0.0057 mole), 0.07 g ofsalicylaldehyde, 6.2 g of acetic acid and 0.02 g of water are stirred at50° C. for 8 hours. The solution obtained in this way contains theracemic salt in a diastereomer ratio of L salt:D salt =49.8:50.2.

D) 6.2 g of quinine, 3.44 g of DL!-homoalanin-4-yl-(methyl)phosphinicacid in 20 ml of acetic acid and 80 ml of methyl isobutyl ketone areheated and slowly cooled to room temperature. During this, 3.1 g of DL!salt of diastereomer ratio L:D=49.6:50.4 crystallize out.

We claim:
 1. A salt of L!- or D!-homoalanin-4-yl(methyl)phosphinic acidand chiral alkaloid bases.
 2. A salt ofL!-homoalanin-4-yl(methyl)phosphinic acid (L acid) and quinine.
 3. Thesalt of L!- or D!-homoalanin-4-yl(methyl)phosphinic acid according toclaim 1 wherein the chiral alkaloid base is quinine, cinchonidine, andbrucine.
 4. The salt of L!- or D!-homoalanin-4-yl(methyl)phosphinic acidaccording to claim 1, wherein the chiral alkaline base is quinine. 5.The salt of L!- or D!-homoalanin-4-yl(methyl)phosphinic acid accordingto claim 1, wherein the chiral alkaline base is cinchonidine.
 6. Thesalt of L!- or D!-homoalanin-4-yl(methyl)phosphinic acid according toclaim 1, wherein the chiral alkaline base is brucine.
 7. The saltaccording to claim 3, wherein the homoalanin-4-yl(methyl)phosphinic acidis in the D!-homoalanin-4-yl(methyl)phosphinic acid.
 8. The saltaccording to claim 7, which is D!-homoalanin-4-yl(methyl)phosphinic acidand quinidine.
 9. The salt according to claim 7, which isD!-homoalanin-4-yl(methyl)phosphinic acid and cinchonine.